1. Field of the Invention
This invention relates to pharmaceutical excipients and more particularly to moldable excipients suitable for preparing dosage forms. The invention also relates to excipients suitable for preparing dosage forms adapted for transmucosal administration of medicaments.
2. Brief Description of the Prior Art
Pharmaceutical compounds are usually administered in the form of mixtures with other ingredients that provide for convenient measurement of the dose, ease in preparation of the dosage form and desirable physical properties of the dosage form such as shape, size, rate of dissolution, and the like. The non-pharmaceutical ingredients of the composition, known as excipients, often constitute the major portion of the composition of which a particular dosage form is composed. In the preparation of a particular dosage form the active pharmaceutical agent is mixed with the excipients in a proportion calculated to provide a desired unit dose in a convenient size and shape. For example, a medicament may be incorporated into a tabletting mixture in a proportion so that a tablet of convenient size made by compressing the mixture will contain one dose of the drug. Similarly, in the case of an ointment for topical application, the proportion of active ingredient mixed with the ointment base will be chosen so that application of a convenient amount of the ointment to the site to be treated will deliver an effective amount of the medication to the site. In addition to providing a means for measuring the dose of medication, the excipient also provides a matrix for containing and releasing the medication to the site to be treated. Thus, an enteric capsule may provide for gradual release of the medication over a period of time in the gastrointestinal tract, or a transdermal matrix may provide for a continuous supply of medication to the skin surface by diffusion through the matrix.
Thus, the proper adaptation of the excipient to the mode and site of delivery of a drug is important in achieving a desired level of the drug in the bloodstream or in securing effective administration of the medication to the desired tissue.
A particular mode of drug delivery wherein the choice of excipient is important is transmucosal administration, particularly in administration via the mucosa of the oral cavity.
Administration of pharmaceutical compounds through the oral mucosa has been found to be an effective means of supplying an effective dose directly to the bloodstream of a patient. The transmucosal route of administration avoids the possibility that the pharmaceutical compound will be destroyed in the gastrointestinal tract before it can be absorbed, and also eliminates the danger of first-pass inactivation in the liver after absorption. Dosage forms relying on transmucosal absorption in the oral cavity have generally been of the buccal or sublingual type. Typically, the buccal dosage form is placed in the buccal cavity between the gum and the cheek, where it dissolves in the patient's saliva, releasing the medicament into the buccal cavity in close proximity to the capillary bed of the oral mucosa. The pharmaceutically active compound then enters the blood in the capillary bed by diffusion through the mucosal tissue and is distributed in the bloodstream to the rest of the body. The rate at which the medication is supplied to the body depends upon, among other things, the rate at which the buccal dosage form dissolves in the mouth. In particular, with patients who have a deficient flow of saliva, a condition found with some frequency in elderly patients and in patients who may be taking medication which tends to depress the flow of saliva, the dosage form may dissolve slowly and supply the medication at a rate which is slower than desired. Such patients also have to endure the discomfort of retaining a foreign object in the buccal cavity, often between the cheek and gum, for a longer period than they might wish.
In sublingual administration, the dosage form is placed beneath the tongue where it dissolves in the saliva to release the drug for transmucosal absorption. A deficiency of this mode of administration is that, in many cases, a significant fraction of the drug released from the dosage form does not remain in contact with the sublingual mucosa long enough to be absorbed, but is washed into the gastrointestinal tract by the continuous flow of saliva. Thus, sublingual medication partakes of the characteristics of both the transmucosal and gastrointestinal routes of administration.
Other methods of administration of medicaments also rely on transmucosal delivery. For example, rectal suppositories and vaginal suppositories or pessaries can be used to deliver drugs to the bloodstream by transmucosal absorption. The physical properties of the dosage form determine the degree of contact with the mucosal tissues and consequently the efficiency of the absorption of the medicament.
Another mode of administration wherein the dosage form is of consequence is in topical administration of medicaments in an ointment. Antimicrobials, antibiotics, antiinflammatory drugs and drugs affecting the skin, such as those used in treating acne, may be administered in this way. Determining the correct dose has been difficult for drugs administered in an ointment, for the material is usually supplied in a tube or jar containing enough for many applications, and the patient must judge how much to apply. In certain applications wherein dosage is critical, this can lead to application of too little medication, with consequent ineffectiveness, or too much, with consequent systemic effects from unwanted transdermal or transmucosal absorption. In some sites, such as the eye or the vagina, uniform application of an ointment is difficult.
Hence, a need has continued to exist for a pharmaceutical excipient that can provide intimate contact with the site to be treated, to assure maximum transmucosal absorption when that is desired, while being capable of being molded into unit dosage forms which retain their shape under conditions of temperature and handling experienced in marketing. In particular, there is a need for a buccal dosage form which will rapidly disintegrate or lose its perceptible shape in the mouth and thereby rapidly and comfortably release its medicament into the buccal cavity independently of the rate of flow of the patient's saliva.